tbuckley/cabot-search huggingface dataset:
P11.63.B Thrombocytopenia limits the feasibility of salvage lomustine chemotherapy in recurrent glioblastoma: a secondary analysis of EORTC 26101
Authors: E Le Rhun, F B Oppong, T Gorlia, M Weller
Journal: Neuro-Oncology (2022)

Abstract Background Chemotherapies used for the treatment of primary brain tumors frequently induce hematological toxicity. Thrombocytopenia represents the main cause of stopping chemotherapy for toxicity. Here we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine chemotherapy at first recurrence of glioblastoma. Methods We performed a retrospective analysis of thrombocytopenia at first recurrence of glioblastoma, its consequences for treatment delivery, and associations with outcome in the phase II and III parts of EORTC 26101, a randomized trial designed to define the role of lomustine versus bevacizumab versus their combination in glioblastoma patients at first relapse. Results 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients of group 1 and 187 patients of group 2 experiencing at least one episode of thrombocytopenia, 36 patients in group 1 and 93 in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. Patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated glioblastoma treated with lomustine alone experienced more interference with study treatment than patients with tumors without MGMT promoter methylation. On adjusted analysis accounting for major prognostic factors, treatment modification by thrombocytopenia was a positive prognostic factor for overall survival, and this effect was entirely driven by patients with tumors without MGMT promoter methylation only. Conversely, thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumors, suggesting a link to insufficient lomustine exposure. Conclusion Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine salvage chemotherapy in patients with recurrent glioblastoma. Its association with survival suggests that mitigating thrombocytopenia to allow enhanced drug exposure in patients with MGMT promoter methylated tumors might improve outcome.
P11.61.B Capecitabine treatment of CNS metastases from breast cancer: intracranial response and survival
Authors: M J A Luitse, G Boles, G S Sonke, D Brandsma
Journal: Neuro-Oncology (2022)

Abstract Background 20-30% of breast cancer patients develop brain metastases (BM) and 5% leptomeningeal metastases (LM). Incidence of BM and/or LM is dependent on breast cancer subtype. Treatment of BM consists of local treatment (resection and/or radiotherapy) and if possible systemic therapy. LM can be treated with radiotherapy of the symptomatic location of the nervous system and/or systemic therapy. Capecitabin is effective for both systemic metastases and BM of HER2-positive breast cancer. The effect of capecitabine in the non-HER2-positive breast cancers and in the LM group is largely unknown. The goal of this study is to determine the intracranial response of capecitabine and survival in HM and/or LM of the various breast cancer subtypes. Material and Methods breast cancer patients with HM and/or LM treated with capecitabine were selected retrospectively from a breast cancer patient cohort treated at the Netherlands Cancer Institute - Antoni van Leeuwenhoek between 2005 and 2020. Follow-up MRI scans of the brains were performed in all patients. The primary endpoints were intracranial response, intracranial progression-free survival (PFS) and overall survival (OS). Subgroup analyses for breast cancer subtypes and BM and LM patient groups were done. Results 93 of 381 patients treated for CNS metastases of breast cancer fulfilled the inclusion criteria. Sixty-one patients (66%) had HM only, 13 (14%) had LM only and 19 patients (20%) had both HM and LM. Forty-six percent of patients had HER2-positive breast cancer, 26% had hormone receptor-positive breast cancer and 28% of patients had a triple negative subtype. After three months of capecitabine treatment intracranial response was 53%. Median OS in the patient group with intracranial response was 16.5 months versus 4.5 months in the non-response group. The hazard ratio (HR) for the median OS, corrected for radiotherapy and concurrently administered, other systemic therapy was 0.33 (95% CI: 0.17-0.67). Median intracranial PFS was 7.3 months in the response group versus 1.4 months in the non-response group (p&amp;lt;0.001).The corrected HR for median intracranial PFS 0.13 (95% CI 0.06-0.27). The HER2-positive subtype group showed the longest median OS (22 months) as compared to the other subtypes (OS in hormone-receptor positive and triple negative subtype both 12 months) Conclusion Fifty-three percent of breast cancer patients with HM and/or LM treated with capecitabine demonstrate an intracranial response after three months of treatment. HER2+ breast cancer patients with HM and/or LM have a longer survival than patients with hormone receptor-positive or triple negative breast cancer subtypes.
P06.03.A Combination of EGFRvIII CAR T cell therapy and paracrine GAM modulation for the treatment of GBM
Authors: T A Martins, N Tatari, M Ritz, T Shekarian, P Schmassmann, D Kaymak, G Hutter
Journal: Neuro-Oncology (2022)

Abstract Background The glioblastoma (GBM) immune microenvironment mainly consists of protumoral glioma-associated microglia and macrophages (GAMs). Previously, we showed that blockade of the don't-eat-me signal CD47, overexpressed by GBM cells, rescued GAMs' phagocytic function in mice. However, CD47 blockade monotherapy has been ineffective in treating human solid tumors to date. Thus, we propose a combinatorial approach of local chimeric antigen receptor (CAR) T cell therapy with paracrine GAM modulation for a synergistic elimination of GBM. Material and Methods We lentivirally transduced healthy donor human T cells to generate humanized EGFRvIII-directed CAR T that constitutively secrete a SIRPγ-related protein (SGRP) with high affinity to CD47. Killing assays were performed with endogenous EGFRvIII-expressing BS153 or EGFRvIII-overexpressed U251 GBM cells and assessed by Incucyte time-lapse imaging analysis. CAR T cell activation was confirmed by flow cytometry (FC) and IFNγ was detected from co-culture supernatants or mouse plasma by ELISA. The CAR T cell secretome was analyzed by liquid chromatography-mass spectrometry (LC-MS) to confirm the secretion of SGRP. NSG mice were orthotopically implanted with either EGFRvIII+ BS153 or U251 cells and treated intratumorally with one or two CAR T cell infusions. Results EGFRvIII and EGFRvIII-SGRP CAR T proliferated and killed tumor cells in vitro in a dose-dependent manner within 72h with complete cytotoxicity at E:T 1:1 compared to CD19 CAR T. CAR T cells specifically co-expressed CD25 and CD107a and secreted IFNγ in the presence of tumor antigen (24h CD25/CD107a co-expression: EGFRvIII=59.3±3.00%, EGFRvIII-SGRP=52.6±1.42%, CD19=0.1±0.07%; 24h IFNγ secretion: EGFRvIII=173.6±2.50%, EGFRvIII-SGRP=113.8±6.42%, CD19=4.5±1.49%). Differential expression analysis of the CAR T cell secretome identified SGRP in EGFRvIII-SGRP CAR T supernatants (-Log10qValue/Log2fold-change=13.72/6.62). Consistent with studies of systemic EGFRvIII CAR T cell therapy, our data suggest that intratumoral EGFRvIII CAR T were insufficient to eliminate BS153 tumors with endogenous EGFRvIII (Overall survival; EGFRvIII: 20%, CD19: 0%, n=5/group). Conclusion Here, we show that EGFRvIII CAR T specifically targeted and killed EGFRvIII+ GBM cells in vitro, but failed to control tumor growth in vivo without GAM modulation. EGFRvIII-SGRP CAR T secretome analysis identified SGRP from the supernatants of unstimulated monocultures. SGRP impaired the binding of SIRPα-Fc to CD47-upregulated GBM cells in vitro, but did not elicit macrophage-mediated phagocytosis of GBM cells in our current in vitro experimental setup. Future work will focus on the functional characterization of SGRP and on further investigating the additive effect of CAR T cell therapy and GAM modulation using translational in vivo and ex vivo models.
P11.19.B Bevacizumab in recurrent WHO grade 2-3 gliomas
Authors: S Annakib, V Rigau, A Darlix, C Gozé, H Duffau, L Bauchet, C Mollevi, M Fabbro
Journal: Neuro-Oncology (2022)

Abstract Background Medical management of recurrent WHO grade 2-3 (rGII/III) gliomas is not well established. Bevacizumab (BEV) is an option at malignant recurrence. Yet, very few data are available in this indication. The aim of this study is to describe clinical outcomes in patients treated with BEV. Material and Methods A retrospective study was conducted including patients treated by BEV for a rGII/III glioma at our institution (2011 - 2019). Data were collected from medical records. Tumor samples were reviewed according to the WHO 2016 classification. Efficacy was assessed according RANO criteria. Progression Free Survival (PFS) and Overall Survival (OS) from BEV initiation were estimated using the Kaplan-Meier method. A Cox proportional hazards model was performed to estimate Hazard Ratios with 95% Confident Intervals (CI). Results A total of 81 patients was included (sex ratio: 1.6 M/W, median age at diagnosis: 38). Among them, 46 patients (56.8%) had a grade 2 and 35 (43.2%) a grade 3 glioma. The histological forms were astrocytoma (grade 2 -3) IDH mutated in 27 patients (33.3%), IDHwt in 15 patients (18.5%) and oligodendroglioma (grade 2 - 3) in 13 patients (16%). Twenty-six patients were not reclassified. Previous treatment included tumor resection for all patients (second intervention in 22.2%). First-line medical treatment consisted of chemotherapy in 60.5% patients before any radiotherapy. Chemotherapy was rechallenged in 52 patients (64.2%). All patients but one received radiation therapy and 19 patients (23.5%) received a reirradiation. BEV was administered at 10 or 15mg/kilogram every 2 or 3 weeks. All patients had a contrast enhancement on MRI at baseline. Median number of BEV cycles was 7 [1-79], in association with chemotherapy in 45.7%. Partial response, stable disease and progressive disease was observed in 27.2%, 22.2% and 50.6% respectively. Median OS from BEV introduction was 7.6 months (95% CI [5.5;9.9]). Median PFS was 4.9 months (95% CI [3.7;6.1]). In univariate analysis, grade 2 (Odd Ratio (OR)=0.41, 95% CI [0.17;1.02], p=0.054), Ki67&amp;lt;7% (OR=0.41, 95% CI [0.15;1.21], p=0.079) and initial total surgical resection (OR=2.75, 95% CI [0.68;11.11], p=0.097) showed a trend for delayed progression. BEV was stopped for progression in 70.4%, for toxicity in 8.6% and for others reasons in 21% patients. Twenty-four patients (29.6%) discontinued BEV without progression (medical decision, BEV toxicity or patient decision). Presence of 1p19q codeletion (OR=0.24, 95% CI [0.07;0.84], p=0.023) and age ≥ 38 (OR=0.36, 95% CI [0.13;0.99], p=0.042) at diagnosis were more frequent in this sub-population. Out these of 24 patients, 8 showed survival from 3 months to 5 years without any other treatment. Conclusion BEV can be a good option for patients with rGII/III glioma. One third of them stopped treatment without progression, reaching a survival of several years for some of them.
P10.06.A Expression of GDNF and its receptors in glioblastoma
Authors: J D Ewald, A M Knudsen, B W Kristensen
Journal: Neuro-Oncology (2022)

Abstract Background Neurotrophic factors are important for brain development, but their role in glioblastoma, the most aggressive primary brain cancer, is not fully understood. We focused on glial cell line-derived neurotrophic factor (GDNF), which has been shown to play a role in growth and migration in glioblastoma. The aim of this study was to investigate the expression of GDNF and its primary receptor GFRA1 as well as GDNF family receptors GFRA2-4 and RET. Material and Methods Tissue sections from 10 glioblastoma patients were stained with antibodies against GDNF (frozen tissue) and each of the receptors (formalin-fixed paraffin-embedded tissue). Moreover, the sections were stained with an RNA Scope assay for GDNF mRNA. The area fractions of positive receptor staining were quantified with a software-based classifier. Double immunofluorescence stainings were performed for GFRA1 and the astrocytic tumor cell marker GFAP, the microglia and macrophage marker IBA1, and the tumor stem cell markers OLIG2 and SOX2, respectively, for assessment of co-expression. Results GDNF staining in a varying number of cells was seen in 5 of the 10 samples. GDNF mRNA stainings were observed in a varying number of cells in all stained tissues, including in hypoxic areas and in microvascular proliferations. Mean area fractions of the receptors were 31 % (range 7-56) for GFRA1, 3 % (0,2-7) for GFRA2, 0,4 % (0,01-2) for GFRA3, 0,1 % (0,02-0,3) for GFRA4 and 1 % (0,1-2) for RET. Co-expression of GFRA1 and GFAP was widely present. Co-expression of GFRA1 and either OLIG2 or SOX2 was partially present. Co-expression of GFRA1 and IBA1 was limited. Conclusion Our results suggest that GDNF and GFRA1 are widely expressed in glioblastoma tissue, but GFRA2-4 and RET are also expressed and may play a role in glioblastoma tumor biology. Future experimental studies are needed to clarify the functional role of GDNF and its receptors in glioblastoma biology.
P15.14.B Radionecrosis versus progression in brain tumors: results of a promising MRI tools
Authors: L Bellu, P Navarria, E Clerici, F Pessina, L Politi, G Savini, S Lillo, M Marzo, M Scorsetti
Journal: Neuro-Oncology (2022)

Abstract Background Distinguish between radiation necrosis (RN) and tumor progression, in patients with irradiated primary or metastatic brain tumors, is a diagnostic challenge. Also the use of new MRI sequences, like diffusion, perfusion-weighted and spectroscopy, or PET with new amino acid tracers, is not always able to differentiate these two entities.To overcome this crucial problem, encouraging results have been obtained using the analysis of delayed contrast extravasation MRI to calculate high resolution maps, called “treatment response assessment maps” (TRAMs). Aim of this exploratory analysis is to assess TRAM ability in differentiate between radiation effect and tumor progression in a small cohort of brain tumor patients treated with radiation therapy (RT). Material and Methods Thirty-four patients irradiated for primary and metastatic brain tumors were evaluated. 12 patients have primary brain tumors, 22 patients have brain metastases from different solid tumors. Distinguish by histological subtypes and type of treatment, the 12 patients with primary brain tumors were: 8 glioblastoma, 2 anaplastic astrocitoma, 1 pleomorphic xanthoastrocytoma WHO grade II, and 1 anaplastic xanthoastrocytoma WHO grade III, treated with surgery followed by RT and concomitant and\or adjuvant chemotherapy with temozolomide. Among brain metastatic patients, primary tumor was: 18 non-small cell lung cancer, 2 malignant melanoma, 1 breast cancer and 1 renal cell carcinoma. All of them were treated with stereotactic radiosurgery at the dose of 20-24Gy in 1fraction, or with hypofractionated stereotactic radiotherapy at the dose of 27-30Gy in 3fractions. All images were uploaded and elaborate into the image workstation ([Brainlab AG, Olof-Palme-Straße 9, 81829 Munich]). TRAMs were calculated by subtracting T1 MRI images acquired 5 minutes after contrast injection from the T1 MRI images acquired 60-105 minutes later. On TRAMs, radiation effects appeared as red areas whereas persistent tumoral lesion appeared as blue areas. Results From February 2021, 34 patients have been evaluated, in a prospective study, with this novel MRI modality. During their follow-up, 13patients (38%) showed a clinicoradiologic suspicion of a persistent tumoral lesion or progressive disease, and 21 (62%) a suspicion of RN. For 14patients a brain MET-PET has been performed. TRAMs analysis have shown a fair agreement with clinicoradiologic diagnosis, perfusion-weighted MRI, and PET imaging. Moreover, 7 patients underwent surgical resection, with histopathological confirm of persistent disease in 4 and radionecrosis in 3. Conclusion These preliminary results show the ability of TRAMs evaluation in distinguish between RN and progressive disease. The recruitment of new patients continues, and further evaluations are ongoing to evaluate sensitivity and positive predictive value of TRAMs analysis.
P07.12.B Brain Biopsy with Optical Guidance
Authors: J Richter, E Klint, K Wårdell
Journal: Neuro-Oncology (2022)

Abstract Background Accurate stereotactic biopsies of brain tumors are imperative for diagnosis and decisions on therapy. Repetitive needle insertions owing to inconclusive tissue samples enhance increased risks of brain lesioning, hemorrhage and prolonged procedure. Previously we reported on frame-based stereotactic biopsies with a combined 5-ALA fluorescence and laser Doppler flowmetry detection system[1]. The system has now been adapted to frameless navigation with a modified biopsy needle and a new registration system[2]. Material and Methods Planning was effected with the Medtronic Stealth System. The optical probe was inserted inside the outer cannula of the biopsy needle, which had an opening at the tip, enabling optical measurements ahead of the needle in real-time while manually forwarding it along the trajectory to the target. Fluorescence spectra, microvascular blood flow, and tissue grayness were recorded during insertion. The biopsies were taken where the fluorescence indicated tumor tissue; the optical probe was replaced by the inner cannula. The diagnoses were compared with the fluorescence signals. Results In the 9 examined patients the fluorescence measurements and pathological diagnosis of high-grade gliomas or lymphomas matched. Only one needle insertion was necessary. The optical measurements along the trajectory took 5-10 min to the target, the pathological diagnosis was reported after 30-70 min. The probe provided direct feedback of increased blood flow along the trajectory and of malignant tissue in the vicinity of the target. Conclusion The optical probe can detect tumor before any tissue is retrieved. If fluorescence is registered, pathological tissue is safely identified. The method can increase the precision and safety of the biopsy and shorten the procedure. The new multimodal probe and the improved registration unit will be tested with other stereotactic and navigation systems and at other neurosurgical centers. Also, the parallel project on fluorescence guided resection of high-grade gliomas is continued[3]. References [1] Johan Richter, Neda Haj-Hosseini, Peter Milos, Martin Hallbeck, Karin Wårdell, (2021), Optical Brain Biopsy with a Fluorescence and Vessel Tracing Probe, Operative Neurosurgery, 217-224, 21(4) [2] Elisabeth Klint, Stina Mauritzon, Bengt Ragnemalm, Johan Richter, Karin Wårdell, (2021), FluoRa - a System for Combined Fluorescence and Microcirculation Measurements in Brain Tumor Surgery, Annual International Conference of the IEEE , 1512-1515 [3] Johan Richter, Neda Haj-Hosseini, Martin Hallbeck, Karin Wårdell, (2017), Combination of hand-held probe and microscopy for fluorescence guided surgery in the brain tumor marginal zone, Photodiagnosis and Photodynamic Therapy, 184-192, 18
P11.67.B Tumor centrality is associated with a declining overall survival in irradiated diffuse glioma
Authors: A T J van der Boog, S David, S H J Nagtegaal, D E Bruil, F Cialdella, T Snijders, P A J Robe, J J C Verhoeff
Journal: Neuro-Oncology (2022)

Abstract Background For diffuse glioma, tumor location is an important factor that influences symptomatology, treatment strategy and, ultimately, survival. Our previous research showed an association between overall survival (OS) and local involvement in eloquent gray and white matter areas in the left hemisphere. Also, involvement of central anatomical structures, such as midline corpus callosum, seem to relate to poorer survival rates, when predefined categories of survival groups (&amp;gt;6 months, 6-24, 24&amp;lt; months) are established. In this study, we investigated OS in relation to centrality of the tumor and its microstructural environment defined as the Clinical Target Volume (CTV) in diffuse glioma treated with radiotherapy in a data-driven fashion. Material and Methods We retrospectively included 273 adult patients with histologically proven diffuse glioma who received first radiotherapy between November 2014 and July 2020 at University Medical Center Utrecht. CTV was spatially normalized to stereotaxic MNI152 space and its center of gravity (CoG) was subsequently calculated. Then, the distance between CoG of CTV to the center of the MNI brain was measured in millimeters (mm) for every tumor. A multivariable Cox-regression model included the distance between CoG of CTV and center of MNI brain, age, sex, total intracranial volume (TIV), Karnofsky Performance Status (KPS), WHO grade and extent of resection. Results During follow-up, 183 patients (67%) deceased and median OS of the population was 13.7 months (range 0.03 - 65.25) from start of radiotherapy. CoG of CTV to center of brain distance had a significantly inverse association with OS in a multivariable Cox-regression model (P &amp;lt; 0.001) with a hazard ratio 0.97 [95% Confidence Interval: 0.95-0.98] per mm. Conclusion In line with literature, centrality of diffuse glioma was associated with a poor survival in irradiated diffuse glioma. In fact, this association was linear, showing a better OS the greater the distance between center of CTV and center of MNI brain after correcting for known prognostic factors such as WHO grade, KPS and extent of resection. Tumor centrality is not a biomarker of involvement in specific eloquent brain regions in and of itself, but a poorer OS in these areas might indicate a proximity to large bulk of commissural white matter tracts and tumor progression along these tracts. Structures of the memory circuit like the fornix and cingulum are also centrally located. Damage to these areas are highly associated with cognitive decline in the memory domain, which is independently related to decreased survival in diffuse glioma patients. Another factor could be tumor involvement of the subventricular zone along the walls of caudate and the lateral ventricles, in which we previously showed that is also associated with worsened survival.